DESCRIPTION: Our principal goal is to discover new anti-HIV clinical trial candidates based on natural products from higher plants. Correspondingly, with the prior support of this grant, we developed the modified triterpene bevirimat (BVM), the first-in-class HIV maturation inhibitor, which successfully reached Phase IIb clinical trials, and discovered the gnidimacrin (GM)-related daphnane-type diterpenes, which exhibit extremely potent dichotomous activity for activation of latent HIV-1 replication and inhibition of de novo HIV infection at low picomolar concentration. We hypothesize that new anti-HIV-1 compounds with unique structures, extremely potent activity, and novel mechanism of action (MOA) can be identified from natural products and their derivatives. We will carry out the following specific studies to accomplish our objectives: 1. Discovery of new leads from natural products. We will identify potent anti-HIV principles from extracts of previously unexplored rainforest and medicinal plant species 2. Optimization of identified leads using rational synthetic modifications to yield promising compounds suitable for future preclinical studies and clinical trials. Two major research areas are 1) Development of a second-generation BVM-analog to overcome issues of Gag polymorphism in the viral target and continue clinical development of triterpenoid maturation inhibitors as a new anti-HIV therapy. 2) Modification of GM-related diterpenes to identify drug candidates for HIV-1 eradication. 3. Determination of anti-HIV-1 activity and MOA for new and already identified promising candidates. We will conduct both HIV drug screening and mechanistic assays, respectively. We plan to identify novel compounds with potent anti-HIV-1 activity and novel MOA, including families of compounds with activity against HIV isolates resistant to currently approved drugs. We also expect to identify the drug targets. A distinctive and valuable collaboration between two academic institutions [Dr. K.H. Lee, Natural Products Research Laboratories (NPRL), UNC and Dr. C.H. Chen, Duke University] has been established and is ongoing to discover and develop novel small molecule HIV inhibitors from natural products and their synthetic analogs. The NPRL has expertise in the bioactivity-directed fractionation and isolation (BDFI) and characterization of bioactive natural products coupled with structural modification of the new leads to optimize their pharmaceutical profiles. Dr. Chen's laboratory at Duke University has the needed expertise, experience, and resources to perform initial activity screening, as well as further mechanistic and pharmacological studies to develop the natural product-based inhibitors through preclinical studies. Based on these current lead compounds as well as future novel active constituents to be identified from medicinal plants, this anti-HIV research program will be able to successfully discover and develop new anti-HIV drug candidates for AIDS treatment and HIV-1 eradication.